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Prevention and therapy of hepatocellular carcinoma by vaccination with TM4SF5 epitope-CpG-DNA-liposome complex without carriers.

ABSTRACT: Although peptide vaccines have been actively studied in various animal models, their efficacy in treatment is limited. To improve the efficacy of peptide vaccines, we previously formulated an efficacious peptide vaccine without carriers using the natural phosphodiester bond CpG-DNA and a special liposome complex (Lipoplex(O)). Here, we show that immunization of mice with a complex consisting of peptide and Lipoplex(O) without carriers significantly induces peptide-specific IgG2a production in a CD4(+) cells- and Th1 differentiation-dependent manner. The transmembrane 4 superfamily member 5 protein (TM4SF5) has gained attention as a target for hepatocellular carcinoma (HCC) therapy because it induces uncontrolled growth of human HCC cells via the loss of contact inhibition. Monoclonal antibodies specific to an epitope of human TM4SF5 (hTM4SF5R2-3) can recognize native mouse TM4SF5 and induce functional effects on mouse cancer cells. Pre-immunization with a complex of the hTM4SF5R2-3 epitope and Lipoplex(O) had prophylactic effects against tumor formation by HCC cells implanted in an mouse tumor model. Furthermore, therapeutic effects were revealed regarding the growth of HCC when the vaccine was injected into mice after tumor formation. These results suggest that our improved peptide vaccine technology provides a novel prophylaxis measure as well as therapy for HCC patients with TM4SF5-positive tumors.

SUBMITTER: Kwon S

PROVIDER: S-EPMC3299740 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Prevention and therapy of hepatocellular carcinoma by vaccination with TM4SF5 epitope-CpG-DNA-liposome complex without carriers.

Kwon Sanghoon S Kim Dongbum D Park Byoung Kwon BK Cho Sunhee S Kim Kwang Dong KD Kim Young-Eun YE Park Cheung-Seog CS Ahn Hyun-Jong HJ Seo Jae-Nam JN Choi Kyung-Chan KC Kim Doo-Sik DS Lee Younghee Y Kwon Hyung-Joo HJ

PloS one 20120312 3

Although peptide vaccines have been actively studied in various animal models, their efficacy in treatment is limited. To improve the efficacy of peptide vaccines, we previously formulated an efficacious peptide vaccine without carriers using the natural phosphodiester bond CpG-DNA and a special liposome complex (Lipoplex(O)). Here, we show that immunization of mice with a complex consisting of peptide and Lipoplex(O) without carriers significantly induces peptide-specific IgG2a production in a ...[more]

PMID: 22427965

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Project description:BackgroundPatients with pancreatic cancer have a poor prognosis and are usually diagnosed at a late stage. Because TM4SF5 is known to be overexpressed in hepatocellular carcinoma, colon cancer, and pancreatic cancer, it is considered as one of the candidate molecular targets for an anticancer strategies.PurposeThe purpose of this study was to evaluate possible utility of TM4SF5 to treat pancreatic cancer using a mouse allograft model.Materials and methodsWe analyzed expression of TM4SF5 in pancreatic cancer tissues using immunohistochemistry. We established a mouse pancreatic cancer cell line stably expressing TM4SF5 and identified the effect of TM4SF5 expression in vitro. We used the CpG-DNA-peptide-liposome complex as a peptide vaccine and investigated antitumor effects of the vaccine in a mouse model with TM4SF5 expressing pancreatic cells. To investigate the function of produced antibody, we evaluated effects of the anti-TM4SF5 monoclonal antibody in vitro in terms of cell growth and migration properties.ResultsImmunohistochemical analysis showed that 36.4% of pancreatic cancer tissue samples expressed TM4SF5. Expression of TM4SF5 induced increased cell proliferation and motility in vitro. Injection of the TM4SF5 peptide vaccine induced the production of anti-hTM4SF5 antibodies and reduced the growth of pancreatic tumors in mice established by subcutaneous injection of the TM4SF5-expressing mouse pancreatic cancer cell line. The treatment of TM4SF5-expressing cells with the anti-hTM4SF5 monoclonal antibody reduced cell growth, modulated the expression of the epithelial-mesenchymal transition markers Vimentin and E-cadherin, and decreased cell motility in vitro.ConclusionOur results showed that the TM4SF5 peptide vaccine had a protective effect against pancreatic tumors expressing TM4SF5, and this effect was mediated, at least in part, by the production and suppressive function of the anti-TM4SF5 antibodies. Therefore, we suggest that targeting TM4SF5 could be a novel strategy to prevent or treat pancreatic cancer.

Dataset Information

Prevention and therapy of hepatocellular carcinoma by vaccination with TM4SF5 epitope-CpG-DNA-liposome complex without carriers.

Publications

Prevention and therapy of hepatocellular carcinoma by vaccination with TM4SF5 epitope-CpG-DNA-liposome complex without carriers.

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